4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide is a pharmaceutical intermediate with the CAS no. 757251-39-1. Its structure is as follows:

4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide is a key intermediate for the anticancer drug Regorafenib. There are generally two types of processes for its synthesis available in the prior art, which are as follows:
Method 1:
It has been reported in the U.S. Pat. No. 8,637,553B that 4-chloro-N-methylpyridine-2-formamide and 4-amino-3-fluorophenol are used as the starting materials to prepare 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide with N, N-dimethyl acetamide as the solvent and an organic base, potassium tert-butoxide, as the base. The reaction scheme was as follows:

The foregoing process uses potassium tert-butoxide as the base in the reaction. As a result, it may easily explode in a large scale industrial production. Therefore, this process is associated with certain security risks. On the other hand, the after treatment of this process needs the processes of concentration, extraction and so on, which may cause great inconvenience in the industrial production and generate a lot of waste water. In particular, the reaction system of this process is in a dark black color, which makes it difficult to distinguish the boundaries between various extraction layers. Moreover, according to the patent disclosures, the highest yield of this process is 77%.
Method 2:
The U.S. Pat. No. 20080090856A reports that the amino group of 4-amino-3-fluorophenol is first protected with a ketone (for example, 2-methyl pentanone), and then it reacts with 4-chloro-N-methylpyridine-2-formamide in the presence of the organic base potassium tert-butoxide, and finally undergoes a de-protection step to prepare the target product, 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide. The reaction scheme was as follows:

The foregoing process has additional steps of adding a protection group and then removing the protection group, which makes the preparation process more cumbersome, especially the second step reaction, which has a yield of merely about 78%.
In view of the various defects present in the synthesis of 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide disclosed in the prior art, providing a low cost and high yield synthesis route for 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide is an urgent problem need to be solved in order to achieve a large scale production of this pharmaceutical product.